Current Hypertension Reports (2019) 21: 22 https://doi.org/10.1007/s11906-019-0924-0 RESISTANT HYPERTENSION (L DRAGER, SECTION EDITOR) Eplerenone Versus Spironolactone in Resistant Hypertension: an Efficacy and/or Cost or Just a Men’sIssue? Antonis A. Manolis1 & Theodora A. Manolis2 & Helen Melita3 & Antonis S. Manolis4 Published online: 2 March 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review To review comparative efficacy and tolerability data between the two main mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, in patients with resistant hypertension (HTN). The focus was whether spironolactone, being the classical non-selective agent that has been used for years, albeit with several anti-androgenic side effects, can be rivaled by eplerenone, an apparently weaker, but better tolerated, more selective MRA. Recent Findings Evidence has accumulated that resistant HTN is generally volume-dependent, attributable to varying degrees of aldosterone excess with its attendant renal effects of sodium and fluid retention. Such aldosteronism may be due to an underestimated occurrence of primary aldosteronism; however, it more commonly occurs separately from it and independent from angiotensin II. The aldosterone-induced volume excess placed at the root of the development of resistant HTN in a large number of patients, together with the extrarenal deleterious effects of aldosterone, such as endothelial dysfunction, vascular remodeling and increased arterial stiffness, cardiac hypertrophy, and fibrosis can all be counterbalanced by the administration of MRAs. In the absence of a direct comparison between spironolactone and eplerenone, and in light of compelling evidence provided by the recently reported results of the PATHWAY-2 and ReHOT studies, spironolactone has been established as the most effective add-on anti-aldosterone therapy in resistant HTN. The data on use of eplerenone continue to emerge and are quite encouraging. Summary Despite the lack of direct comparative data, the weight of evidence regarding efficacy is currently in favor of spironolactone. However, the data on the efficacy of eplerenone are promising but still being accumulated suggesting this agent as an alternative to spironolactone and certainly as the preferred choice for those not tolerating spironolactone, especially for patients developing anti-androgenic side effects like breast tenderness, gynecomastia/mastodynia, and/or sexual dysfunction. Both these agents appear to have several other pleiotropic effects that confer cardioprotection and renoprotection beyond their antihypertensive effect. Potassium levels and renal function need to be closely monitored during administration of these therapies. Future comparative studies may shed more light on these issues, while emerg- ing newer agents may offer better and safer therapeutic options. Keywords Hypertension . Resistant hypertension . Aldosterone . Aldosteronism . Spironolactone . Eplerenone . Mineralocorticoid receptor antagonist . Heart failure Abbreviations This article is part of the Topical Collection on Resistant Hypertension ACE Angiotensin-converting enzyme AF Atrial fibrillation * Antonis S. Manolis ARB Angiotensin receptor blocker [email protected] BP Blood pressure 1 CKD Chronic kidney disease Patras University School of Medicine, Patras, Greece CV Cardiovascular 2 Red Cross Hospital, Athens, Greece eGFR Estimated glomerular filtration rate 3 Onassis Cardiac Surgery Center, Athens, Greece HF Heart failure 4 Third Department of Cardiology, Athens University School of HTN Hypertension Medicine, Vas. Sofias 114, 115 27 Athens, Greece LV Left ventricle(-ular) 22 Page 2 of 14 Curr Hypertens Rep (2019) 21: 22 LVEF Left ventricular ejection fraction HTN [2]. The effectiveness of antihypertensive therapy with LVH Left ventricular hypertrophy MRAs apparently attests to the plethora of observations indi- MI Myocardial infarction cating a significant role of aldosterone in contributing to re- MRA Mineralocorticoid receptor antagonist sistant or difficult to treat HTN [11, 12, 13•, 14•, 15•]. NYHA New York Heart Association Aldosterone excess occurring separately from PA and inde- PA Primary aldosteronism pendent from angiotensin II may have several causes, includ- RAAS Renin–angiotensin–aldosterone system ing, but not limited to, obesity and/or sleep apnea [2, 16, 17]. RAS Renin–angiotensin system Beyond sodium reabsorption in the distal nephron of the RCT Randomizedcontrolledtrial kidney, aldosterone exerts several other effects on the kidney, SCD Sudden cardiac death heart, and vasculature (Fig. 1)[18, 19]. Several studies have indicated an important role of aldosterone in the pathophysi- ological mechanism of target-organ damage encountered in Introduction hypertensive disease [18, 20]. Aldosterone has been implicat- ed in left ventricular hypertrophy (LVH), renal injury, vascular Spironolactone was the first mineralocorticoid receptor antag- disease [21–24], atrial (atrial fibrillation/flutter), and ventricu- onist (MRA) available for the treatment of hypertension lar arrhythmias [25] and structural and functional changes of (HTN) and heart failure (HF) [1•]. Eplerenone was the second medium-sized arteries [26], as well as microcirculation inju- MRA that received Food and Drug Administration (FDA) ries and endothelial dysfunction [27–29]. Hence, the impetus approval 15 years ago for the same indications. Aldosterone, has emerged to counter these deleterious effects with use of part of the renin–angiotensin–aldosterone system (RAAS), MRAs in hypertensive patients. has been linked to HTN, cardiac hypertrophy, and cardiac and vascular fibrosis [2]. Despite treatment with an angiotensin-converting enzyme (ACE) inhibitor or angioten- MRAs in Hypertension sin II receptor blocker (ARB), suppression of aldosterone is not complete due to non-angiotensin II regulators of aldoste- Spironolactone A longer experience with MRAs in HTN rone production, such as serum potassium. therapy exists for spironolactone, which has been used Spironolactone is a non-selective MRA that has progesta- with or without a thiazide diuretic to treat mild to moder- tional and anti-androgenic adverse effects due to its nonspe- ate HTN and more recently as add-on therapy for resistant cific binding to various steroid receptors. Eplerenone is a more HTN [30–34]. selective inhibitor of the mineralocorticoid receptor, with up to A meta-analysis of 5 crossover trials (n = 137) and of 1 a 500-fold lower affinity for the androgen and progestin re- RCT (n = 42) studying patients with primary HTN followed ceptors that leads to fewer side effects [3]. Other non-steroidal for 4–8 weeks of therapy found a reduction in systolic blood MRAs (finerenone, apararenone, esaxerenone) are in clinical pressure (BP) of 20.09 mmHg (p < 0.00001) and a 6.75- trials in patients with HTN, HF, chronic kidney disease mmHg (p < 0.00001) reduction in diastolic BP [35•]. There (CKD), and liver disease [1•]. MRAs have proven efficacy was no evidence of heterogeneity between the studies. It ap- in patients with resistant HTN, considered as one of the best peared that doses > 50 mg/day did not produce further reduc- pharmacologic options in this subgroup of patients [4, 5]. As tions in either systolic BP or diastolic BP. One crossover study detailed below, a milestone randomized controlled trial found that spironolactone 25 mg/day did not statistically sig- (RCT), the PATHWAY-2 study, demonstrated that nificantly change systolic or diastolic BP compared to place- spironolactone was the most effective drug added to a stan- bo. The authors concluded that spironolactone appears to low- dard three-drug regimen in the treatment of resistant HTN er BP compared to placebo at reasonable doses of 25 to [6••], while another more recent study (ReHOT) indicated that 100 mg/day. There was no evidence of the effect of spironolactone is preferable as the fourth drug for the treat- spironolactone on clinical outcomes in hypertensive patients. ment of resistant HTN [7•]. Eplerenone Eplerenone has also been used effectively in man- aging patients with mild/moderate HTN [36, 37, 38•, 39]. The Deleterious Effects of Aldosterone antihypertensive effect of eplerenone has been shown to be in Hypertensive Patients equal in black and white patients and even superior to an ARB in black patients [40]. According to a meta-analysis of 11 Aldosterone excess has been commonly documented in pa- randomized clinical trials assessing eplerenone in > 3500 hy- tients with resistant HTN [8•, 9•, 10]. Furthermore, primary pertensives with mild to moderate HTN, eplerenone is an ef- aldosteronism (PA) may be more common than what was fective antihypertensive agent when used alone or in combi- previously thought, particularly in patients with resistant nation with other medications [41•]. In doses of 25–100 mg Curr Hypertens Rep (2019) 21: 22 Page 3 of 14 22 Fig. 1 Production and effects of aldosterone. Aldosterone is produced in and are directly implicated in the development of resistant hypertension. the zona glomerulosa of the adrenal cortex in response to angiotensin II, ACTH = adrenocorticotropin hormone; ACE = angiotensin-converting increased serum potassium, and corticotropin (ACTH). It regulates total enzyme; AT1R = angiotensin II type-1 receptor. body sodium (Na+) and potassium (K+) balance by binding and *Extrarenal effects: in the heart (pro-arrhythmia/electrical ionic activating mineralocorticoid receptors in the distal collecting